Ophthalmic composition containing an anesthetic and fluorescein sodium



United States Patent 3,306,820 OPHTHALMIC COMPOSITION CONTAINING AN ANESTHETHC AND FLUORESCEIN SODIUM Joseph Z. Krezauoski, Sunnyvale, Calif., assignor to Barnes-Hind Pharmaceuticals, Inc., a corporation of California No Drawing. Filed Mar. 18, 1966, Ser. No. 535,365 4 Claims. (Cl. 16759) This application is a continuation-in-part of my application Serial No. 399,066, filed September 24, 1964, now abandoned.

This invention relates to a combination anesthetic and disclosing agent for ophthalmic purposes. Although the composition of the present invention is primarily adapted for use in combination with an applanation tonometer, and such use will be described herein, it is obvious that the composition can be used in any situation wherein a combination of local anesthetic and disclosing agent is needed in an ophthalmic procedure, e.g., for the location of a foreign body.

In the use of the applanation tonometer, it is ncces' sary to use both a disclosing agent, which is ordinarily fiuorescein sodium, and an anesthetic. Heretofore, it has been necessary to employ two separate solutions, which is inconvenient to the patient and time consuming on the part of the examining physician. If one merely attempted to combine the usual local anesthetics with fiuorescein, a precipitate would be formed. This precipitate consists in part of fiuorescein, which has only very limited solubility at pH values below 6.0, and in part of an insoluble fluoresceinate salt of the local anesthetic. The local anesthetics suited for ophthalmological use, including benoxinate, proparacaine, and tetracaine, require pH values of or lower for maximum stability and shelf life.

In accordance with the present invention, it has been found that certain specific anesthetics can be combined with fiuorescein sodium by the employment of polyvinylpyrrolidone as a complexing and solubilizing agent so that the solution is stable for long periods of time and can be adjusted to a physiologically tolerated pH so that little or no irritation occurs when the material is instilled in the eye. One of the principal problems overcome by the present invention, therefore, is solubilization of fiuorescein and a local anesthetic-fiuoresceinated salt at pH 5. In carrying out the invention, it is also important that the local anesthetic be one which does not injure the cornea or render the corneal surface liable to staining by the fiuorescein. If the corneal surface becomes stained by the fiuorescein, a false reading will be obtained from the tonometer since it is then impossible to determine the exact area which is in contact with the prism. Another prerequisite of this invention is that the solubilizing agent does not promote wetting of the plastic applanation plate when it is brought against the cornea during the applanation tonometer pressure determination. Should wetting and spreading occur, the eniscus disclosing the diameter of applanation would be destroyed. Suitable anesthetics are proparacaine, parethoxycaine, benoxinate and tetracaine.

In carrying out the invention, a solution is made containing from 0.05% to 0.3% of fiuorescein sodium, a concentration of from 5% to 15%, preferably 15%, of polyvinylpyrrolidone, and from 0.1% to 2.0% of the selected local anesthetic. In addition, a non-toxic acid such as citric acid or, preferably, boric acid is employed to adjust the pH to 5 and as the balance, distilled water is employed. As has been mentioned above, not all local anesthetics are suitable for use in the present invention, since some of them render the corneal surface Patented Feb. 28, 1967 "ice liable to staining, while others are incompatible with fiuorescein sodium even in the presence of polyvinylpyrrolidone. Still other local anesthetics lack the necessary stability at physiologically tolerated pH values.

A product so formulated may be used without the employment of a preservative against contamination, particularly if it is packaged in a single dosage container. However, when the product is packaged in multiple use sized containers, it is preferable to employ an antimicrobial agent which prevents contamination which might result from exposure to air or from other sources after the container is opened. Although a combination of phenylmercuric acetate and chlorobutanol may be employed, it is preferred to employ chlorobutanol alone as the preservative since it has been found to give superior long-term antimicrobial stability. Ordinarily chlorobutanol has a solubility of only about 0.8% in an aqueous system, but it has been found that the polyvinylpyrrolidone solubilizes the chlorobutanol so that up to 1.4% may be used. From 0.5% to 1.4% of chlorobutanol may be employed and it is preferred to employ about 1.2%.

The following working examples typify embodiments of the present invention:

Fluorescein Plasdone C,* Example Anesthetic Sodium, percent percent 1 Proparacaine, HCl 0.5%..- 0.05 5. 0 2 "do 0. 05 10. 0 3 0.05 15.0 4 0. 1 5. 0 5 0. 1 10. 0 6 O. 1 15. 0 7 0. 5 15. 0 8 (lo 0.25 10.0 9 arethoxycaine, HCl 2.0% 0. 1 10. 0 l0 Parethoxycaine, HCl 2.0%.. 0. 5 10. 0 ll Benoxinate, HCl 0.5% 0.1 10. 0 12 Tetracaine, I-ICl 0.5% 0.25 15. 0

* Generic name is polyviuylpyrrolidonc, pharmaceutical grade.

Each of the above compositions also contained the following:

Percent Phenylmercuric acetate 0.004 Chlorobutanol 0.5

Boric acid or citric acid to adjust pH to 5 (about 1% boric acid or 0.3% citric acid is required).

Percent Distilled water, q.s. to

A preferred formulation is as follows:

Sodium fiuorescein 0.25 Benoxinate hydrochloride 0.4 Polyvinylpyrrolidone 15 Chlorobutanol 1.2 Boric acid, q.s. to pH 5.0 water, q.s 100 The above compositions have been tested and found effective for the combined function of disclosing agent and local anesthetic. All of these compositions remain stable in storage for long periods of time (1-3 years), do not render the cornea liable to staining, and are substantially non-irritating to the eye. Furthermore, the precision of the intraocular pressure determination using ap- F planation tonometry is not influenced.

The above formulations have been evaluated with respect to eye irritation and reactions, pain on application, level of anesthesia, degree of fluorescence, and accuracy of tonometer reading. It has been used in each eye in the course of 3,000 patient visits during which applanation tonometry was performed. The product has also been compared to agents now being used in preparation for applanation tonometry.

Eye irritation is infrequent. When it occurs, it is transient and is comparable to that which occurs with the anesthetic preparations now available. No systemic reactions have been noted.

Pain on application is mild or non-existent. By comparing with the opposite eye, pain has been found to be the same as with the usual 0.5% proparacaine solution.

Depth of anaesthesia has been adequate in each case for tonometry and other corneal manipulations, such as foreign body removal. The average time for onset of anaesthesia is less than fifteen seconds and anaesthesia lasts for at least fifteen minutes.

Fluorescence has been entirely satisfactory. The present formulation using polyvinylpyrrolidone actually seems to enhance fluorescence. Concentrations of fluorescein as low as 0.05% were used effectively with the Goldmann model 900 slit lamp. Concentrations below 0.25% are not as effective with the lower light intensity available from the older model Haag-Streit slit lamp.

Accuracy of tonometer readings was determined by measuring the tension first using proparacaine and the usual fluorescein strips. This was followed by an application of the above formulation and repeat tonometry. Repeated measurements in this manner failed to show any error introduced by the above formulation.

Although it is not ordinarily necessary, in some instances it may be desired to incorporate a chelating agent in the formulation. In this purpose disodium EDTA (disodium ethylene diamine tetraacetic acid) in a concentration of about 0.1% is suitable.

Iclaim:

1. A combination ophthalmic local anesthetic and disclosing agent comprising a local anesthetic selected from proparacaine, parethoxycaine, benoxinate or tetracaine,

fluorescein sodium, and polyvinylpyrrolidone wherein the local anesthetic is present in a concentration of from 0.1% to 2.0%, the fluorescein sodium is present in a concentration of from 0.05% to 0.3% and the polyvinylpyrrolidone is present in a concentration of from 5% to 15%, the balance of the composition consisting essentially of distilled water and having a pH of about 5.0.

2. A combination ophthalmic local anesthetic and disclosing agent in accordance with claim 1 containing an antimicrobial agent.

3. The composition of claim 2 wherein the antimicrobial agent comprises chlorobutanol.

4. A combination ophthalmic local anesthetic and disclosing agent in accordance with claim 1 containing the following:

Percent Sodium fluorescein 0.25 Benoxinate hydrochloride 0.4 Polyvinylpyrrolidone 15 Chlorobutanol 1.2 Boric acid, q.s. to pH 5.0 water, q.s.

References Cited by the Examiner PVP, Polyvinylpyrrolidone, booklet No. 15 M857- 2.5 M- Exp. 1957, pp. 21, 25, 26.

Schradie: Practical Pharmacy Edition, vol. 20, No. 4, April 1959, pp. l97l99.

Pan: American I. of Ophthal, vol. 56, No. 4, October 1963, p. 686.

Brit. J. Ophthal, vol. 48, p. 633, 1964.

The Merck Index of Chemicals and Drugs, Merck and Co., Inc., 7th ed., Rahway, N.J., 1960, pp. 127, 455, 557, 859 and 1020.

JULIAN S. LEV ITT, Primary Examiner.

JEROME D. GOLDBERG, Assistant Examiner. 

1. A COMBINATION OPHTHAMINIC LOCAL ANESTHETIC AND DISCLOSING AGENT COMPRISING A LOCAL ANESTHETIC SELECTED FROM PROPARACAINE, PARETHOXYCAINE, BENOXINATE OR TETRACAINE, FLUORESCEIN SODIUM, AND POLYVINLYPYRROLIDONE WHEREIN THE LOCAL ANESTHETIC IS PRESENT IN A CONCENTRATION OF FROM 0.1% TO 2.0%, THE FLUORESCEIN SODIUM IS PRESENT IN A CONCENTRATION OF FROM 0.05% TO 0.3% AND THE POLYVINYLPYRROLIDONE IS PRESENT IN A CONCENTRATION OF FROM 5% TO 15%, THE BALANCE OF THE COMPOSITION CONSISTING ESSENTIALLY OF DISTILLED WATER AND HAVING A PH OF ABOUT 5.0. 